Tetraspanin 5 (TSPAN5), a Novel Gatekeeper of the Tumor Suppressor DLC1 and Myocardin-Related Transcription Factors (MRTFs), Controls HCC Growth and Senescence

Human hepatocellular carcinoma (HCC) is among the most lethal and common cancers in the human population, and new molecular targets for therapeutic intervention are urgently needed. Deleted in liver cancer 1 (DLC1) was originally identified as a tumor suppressor gene in human HCC. DLC1 is a Rho-GTPa...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Laura Schreyer, Constanze Mittermeier, Miriam J. Franz, Melanie A. Meier, Dietmar E. Martin, Kerstin C. Maier, Kerstin Huebner, Regine Schneider-Stock, Stephan Singer, Kerstin Holzer, Dagmar Fischer, Silvia Ribback, Bernhard Liebl, Thomas Gudermann, Achim Aigner, Susanne Muehlich
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	DLC1 TSPAN5 MKL1 MRTF SRF Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/9a46f0305c3f4da6928cc0db1f054c25
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:9a46f0305c3f4da6928cc0db1f054c25
record_format	dspace
spelling	oai:doaj.org-article:9a46f0305c3f4da6928cc0db1f054c252021-11-11T15:29:29ZTetraspanin 5 (TSPAN5), a Novel Gatekeeper of the Tumor Suppressor DLC1 and Myocardin-Related Transcription Factors (MRTFs), Controls HCC Growth and Senescence10.3390/cancers132153732072-6694https://doaj.org/article/9a46f0305c3f4da6928cc0db1f054c252021-10-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5373https://doaj.org/toc/2072-6694Human hepatocellular carcinoma (HCC) is among the most lethal and common cancers in the human population, and new molecular targets for therapeutic intervention are urgently needed. Deleted in liver cancer 1 (DLC1) was originally identified as a tumor suppressor gene in human HCC. DLC1 is a Rho-GTPase-activating protein (RhoGAP) which accelerates the return of RhoGTPases to an inactive state. We recently described that the restoration of DLC1 expression induces cellular senescence. However, this principle is not amenable to direct therapeutic targeting. We therefore performed gene expression profiling for HepG2 cells depleted of DLC1 to identify druggable gene targets mediating the effects of DLC1 on senescence induction. This approach revealed that versican (VCAN), tetraspanin 5 (TSPAN5) and N-cadherin (CDH2) were strongly upregulated upon DLC1 depletion in HCC cells, but only TSPAN5 affected the proliferation of HCC cells and human HCC. The depletion of TSPAN5 induced oncogene-induced senescence (OIS), mediated by the p16<sup>INK4a</sup>/pRb pathways. Mechanistically, silencing TSPAN5 reduced actin polymerization and thereby myocardin-related transcription factor A- filamin A (MRTF-A-FLNA) complex formation, resulting in decreased expression of MRTF/SRF-dependent target genes and senescence induction in vitro and in vivo. Our results identify TSPAN5 as a novel druggable target for HCC.Laura SchreyerConstanze MittermeierMiriam J. FranzMelanie A. MeierDietmar E. MartinKerstin C. MaierKerstin HuebnerRegine Schneider-StockStephan SingerKerstin HolzerDagmar FischerSilvia RibbackBernhard LieblThomas GudermannAchim AignerSusanne MuehlichMDPI AGarticleDLC1TSPAN5MKL1MRTFSRFNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5373, p 5373 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	DLC1 TSPAN5 MKL1 MRTF SRF Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	DLC1 TSPAN5 MKL1 MRTF SRF Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Laura Schreyer Constanze Mittermeier Miriam J. Franz Melanie A. Meier Dietmar E. Martin Kerstin C. Maier Kerstin Huebner Regine Schneider-Stock Stephan Singer Kerstin Holzer Dagmar Fischer Silvia Ribback Bernhard Liebl Thomas Gudermann Achim Aigner Susanne Muehlich Tetraspanin 5 (TSPAN5), a Novel Gatekeeper of the Tumor Suppressor DLC1 and Myocardin-Related Transcription Factors (MRTFs), Controls HCC Growth and Senescence
description	Human hepatocellular carcinoma (HCC) is among the most lethal and common cancers in the human population, and new molecular targets for therapeutic intervention are urgently needed. Deleted in liver cancer 1 (DLC1) was originally identified as a tumor suppressor gene in human HCC. DLC1 is a Rho-GTPase-activating protein (RhoGAP) which accelerates the return of RhoGTPases to an inactive state. We recently described that the restoration of DLC1 expression induces cellular senescence. However, this principle is not amenable to direct therapeutic targeting. We therefore performed gene expression profiling for HepG2 cells depleted of DLC1 to identify druggable gene targets mediating the effects of DLC1 on senescence induction. This approach revealed that versican (VCAN), tetraspanin 5 (TSPAN5) and N-cadherin (CDH2) were strongly upregulated upon DLC1 depletion in HCC cells, but only TSPAN5 affected the proliferation of HCC cells and human HCC. The depletion of TSPAN5 induced oncogene-induced senescence (OIS), mediated by the p16<sup>INK4a</sup>/pRb pathways. Mechanistically, silencing TSPAN5 reduced actin polymerization and thereby myocardin-related transcription factor A- filamin A (MRTF-A-FLNA) complex formation, resulting in decreased expression of MRTF/SRF-dependent target genes and senescence induction in vitro and in vivo. Our results identify TSPAN5 as a novel druggable target for HCC.
format	article
author	Laura Schreyer Constanze Mittermeier Miriam J. Franz Melanie A. Meier Dietmar E. Martin Kerstin C. Maier Kerstin Huebner Regine Schneider-Stock Stephan Singer Kerstin Holzer Dagmar Fischer Silvia Ribback Bernhard Liebl Thomas Gudermann Achim Aigner Susanne Muehlich
author_facet	Laura Schreyer Constanze Mittermeier Miriam J. Franz Melanie A. Meier Dietmar E. Martin Kerstin C. Maier Kerstin Huebner Regine Schneider-Stock Stephan Singer Kerstin Holzer Dagmar Fischer Silvia Ribback Bernhard Liebl Thomas Gudermann Achim Aigner Susanne Muehlich
author_sort	Laura Schreyer
title	Tetraspanin 5 (TSPAN5), a Novel Gatekeeper of the Tumor Suppressor DLC1 and Myocardin-Related Transcription Factors (MRTFs), Controls HCC Growth and Senescence
title_short	Tetraspanin 5 (TSPAN5), a Novel Gatekeeper of the Tumor Suppressor DLC1 and Myocardin-Related Transcription Factors (MRTFs), Controls HCC Growth and Senescence
title_full	Tetraspanin 5 (TSPAN5), a Novel Gatekeeper of the Tumor Suppressor DLC1 and Myocardin-Related Transcription Factors (MRTFs), Controls HCC Growth and Senescence
title_fullStr	Tetraspanin 5 (TSPAN5), a Novel Gatekeeper of the Tumor Suppressor DLC1 and Myocardin-Related Transcription Factors (MRTFs), Controls HCC Growth and Senescence
title_full_unstemmed	Tetraspanin 5 (TSPAN5), a Novel Gatekeeper of the Tumor Suppressor DLC1 and Myocardin-Related Transcription Factors (MRTFs), Controls HCC Growth and Senescence
title_sort	tetraspanin 5 (tspan5), a novel gatekeeper of the tumor suppressor dlc1 and myocardin-related transcription factors (mrtfs), controls hcc growth and senescence
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/9a46f0305c3f4da6928cc0db1f054c25
work_keys_str_mv	AT lauraschreyer tetraspanin5tspan5anovelgatekeeperofthetumorsuppressordlc1andmyocardinrelatedtranscriptionfactorsmrtfscontrolshccgrowthandsenescence AT constanzemittermeier tetraspanin5tspan5anovelgatekeeperofthetumorsuppressordlc1andmyocardinrelatedtranscriptionfactorsmrtfscontrolshccgrowthandsenescence AT miriamjfranz tetraspanin5tspan5anovelgatekeeperofthetumorsuppressordlc1andmyocardinrelatedtranscriptionfactorsmrtfscontrolshccgrowthandsenescence AT melanieameier tetraspanin5tspan5anovelgatekeeperofthetumorsuppressordlc1andmyocardinrelatedtranscriptionfactorsmrtfscontrolshccgrowthandsenescence AT dietmaremartin tetraspanin5tspan5anovelgatekeeperofthetumorsuppressordlc1andmyocardinrelatedtranscriptionfactorsmrtfscontrolshccgrowthandsenescence AT kerstincmaier tetraspanin5tspan5anovelgatekeeperofthetumorsuppressordlc1andmyocardinrelatedtranscriptionfactorsmrtfscontrolshccgrowthandsenescence AT kerstinhuebner tetraspanin5tspan5anovelgatekeeperofthetumorsuppressordlc1andmyocardinrelatedtranscriptionfactorsmrtfscontrolshccgrowthandsenescence AT regineschneiderstock tetraspanin5tspan5anovelgatekeeperofthetumorsuppressordlc1andmyocardinrelatedtranscriptionfactorsmrtfscontrolshccgrowthandsenescence AT stephansinger tetraspanin5tspan5anovelgatekeeperofthetumorsuppressordlc1andmyocardinrelatedtranscriptionfactorsmrtfscontrolshccgrowthandsenescence AT kerstinholzer tetraspanin5tspan5anovelgatekeeperofthetumorsuppressordlc1andmyocardinrelatedtranscriptionfactorsmrtfscontrolshccgrowthandsenescence AT dagmarfischer tetraspanin5tspan5anovelgatekeeperofthetumorsuppressordlc1andmyocardinrelatedtranscriptionfactorsmrtfscontrolshccgrowthandsenescence AT silviaribback tetraspanin5tspan5anovelgatekeeperofthetumorsuppressordlc1andmyocardinrelatedtranscriptionfactorsmrtfscontrolshccgrowthandsenescence AT bernhardliebl tetraspanin5tspan5anovelgatekeeperofthetumorsuppressordlc1andmyocardinrelatedtranscriptionfactorsmrtfscontrolshccgrowthandsenescence AT thomasgudermann tetraspanin5tspan5anovelgatekeeperofthetumorsuppressordlc1andmyocardinrelatedtranscriptionfactorsmrtfscontrolshccgrowthandsenescence AT achimaigner tetraspanin5tspan5anovelgatekeeperofthetumorsuppressordlc1andmyocardinrelatedtranscriptionfactorsmrtfscontrolshccgrowthandsenescence AT susannemuehlich tetraspanin5tspan5anovelgatekeeperofthetumorsuppressordlc1andmyocardinrelatedtranscriptionfactorsmrtfscontrolshccgrowthandsenescence
_version_	1718435256768397312

Tetraspanin 5 (TSPAN5), a Novel Gatekeeper of the Tumor Suppressor DLC1 and Myocardin-Related Transcription Factors (MRTFs), Controls HCC Growth and Senescence

Ejemplares similares